In respiratory failure with hypercapnea/acidosis, consider BiPAP or intubation

Intravenous antibiotics covering the patient's prior cultures; if unknown, cover most common bacteria including Pseudomonas aeruginosa and Staphylococcus aureus

If massive hemoptysis (> 400 cc and it does not stop), prepare for bronchial artery embolization or resection (rarely used); bronchoscopy has limited utility in such settings

Airway clearance in the form of manual chest physical therapy to mobilize and remove secretions should be initiated using manual chest physical therapy (in critically ill patients), supplemented by percussion VEST or other PEP devices

Use of mucous active agents by nebulization, including dornase-alpha (1 or 2 times daily), hypertonic saline (3-10%, up to 4 times daily) and N-acetylcysteine (no good evidence to support its use)

Nebulized antibiotics including tobramycin for inhalation, colistin or aztrenam lysinate for inhalation.

Some patients with specific mutations (most common are G551D and R117H) benefit from the oral medication ivacaftor, which improves CFTR function and as a result ameliorates most of the disease manifestations. Ivacaftor should be continued in these patients.

Another CFTR modifier for patients with the most common mutation combination (DF508 homozygotes; 40-45% of all adults with CF) is lumacaftor/ivacaftor and has the same benefits in modifying CFTR function, although not as pronounced as ivacaftor for the patients in the previous paragraph. It should also be continued.

3. Diagnosis

CF remains primarily a clinical diagnosis. The main organ systems being affected are as follows:

Manifestations as side effects of treatment:

3. Hearing loss (as a result of frequent aminoglycosides).
Gold standard for diagnosis is sweat chloride; values over 60 are consistent with CF, values between 40 and 59 are borderline.

Genetic testing provides confirmation. There are 23 CF-causing known CFTR mutations and when two of these are found CF can be diagnosed; there are more than 2000 non-CF-causing CFTR mutations. If two of these or one of them is found with the 23 mutations, CF can only be confirmed by the sweat test and highly suggestive clinical manifestations.

These 1900+ mutations are either too rare to be 100% certain of their clinical manifestations or do not always cause severe enough alterations in CFTR to cause CF.

Isolated elevations in alkaline phosphatase can be seen in patients even without significant liver disease (up to 20% of patients).

During exacerbations, elevations in WBC, CRP and ESR are common.

Insulin resistance with high blood sugars and high insulin requirements are common during acute exacerbations; however, ketoacidosis almost never occurs.

PT and INR can be normal, but may still have vitamin K deficiency.

In patients with ABPA, high eosinophil levels and IgE can occur.

After a period of antibiotic therapy it is not uncommon to see modest elevations in eosinophilia; its clinical significance is unknown.

CXR shows bronchiectasis.

In patients with abdominal obstruction syndrome, DIOS is the most common and manifests with mild or no obstructive signs on abdominal X-ray, but large amounts of stool are seen in the right colon and terminal ileum.

In patients with pneumothorax it can be seen on CXR, although frequently it is loculated because of adhesions.

In patients with hemoptysis findings similar to exacerbation with or without alveolar infiltrates can be seen.

CT chest is useful in hemoptysis in assessing laterality and can be useful in respiratory exacerbation to assess extent of the disease.

Hemoptysis with > 30 cc per day is also a common presenting sign, particularly in those with advanced disease. CF exacerbations are more common in patients who have more severe baseline disease and in those who have a history of poor adherence to therapies.

Sudden onset of symptoms accompanied by chest pain suggests pneumothorax as a cause. This is also more common in patients with severe disease.

If the patient presents with abdominal pain the most likely cause will be distal intestinal obstruction syndrome (DIOS), which is a meconium ileus of the adult. The patient will have abdominal pain, which can be severe, decreased but not necessarily absent bowel movements, nausea, decreased appetite and occasionally vomiting.

The abdominal exam might even show rebound, but bowel sounds will be present. Labs will not point to a liver or pancreatic source and the white blood cell count is often mildly elevated. The abdominal x-ray will show a large amount of stool, especially in the right colon, with or without features of obstruction (not-infrequently, radiology fails to recognize this condition).

The condition occurs in pancreatic-insufficient patients, usually in the setting of changes in pancreatic enzyme supplementation, or poorly controlled diabetes or relative dehydration (for example, being out in the summer heat).

Other diagnoses that need to be entertained include pulmonary embolism, especially in debilitated patients with indwelling catheters,and in those with catheters - septic emboli. These are not as common. Cardiac causes, especially left-sided heart failure, would be highly unlikely in this population and fluid overload would be a likely cause only if there is concomitant renal failure.

Other gastrointestinal causes that can lead to ICU admission include appendicitis, cholecystitis (sometimes without obvious stones, but with significant biliary sludge) and acute pancreatitis in pancreatic-sufficient patients. In children and young adults intussusception can also occur, it can occur in setting of colon cancer which is more common in patients with CF. The first two issues are difficult to recognize and require further testing; pancreatitis is easy to identify by an elevation in pancreatic enzymes.

For patients who present with pulmonary symptoms and signs requiring ICU care need a chest x-ray and sometimes a CT chest with contrast to assess for pulmonary embolism; upper and lower extremity ultrasound can also help confirm DVT.

For patients with GI presentations an abdominal x-ray is needed and appropriate labs. If a diagnosis cannot be established, then an ultrasound of theg allbladder would help and occasionally a HIDA scan might be needed. CT abdomen or US could also help determine the diagnosis of appendicitis.

4. Specific Treatment

Pulmonary exacerbations require the following:

1. Aggressive hydration to help hydrate the secretions and make them easier to mobilize;

4. Prepare for pleurodesis in most cases, since pneumothoraces tend to recur; for appropriate method need to consider disease severity and local surgical preference (since pleurodesis is a relative contraindication for lung transplant in most situations).

DIOS treatment requires the following:

1. Aggressive hydration;

2. Use of Miralax or other PEG solutions by mouth or NG tube or G-tube if available in sufficient amount to induce stooling (usually more than a gallon needed) if patient not vomiting;

4. Consider allergic bronchopulmonary aspergillosis as the diagnosis and treat with steroids.
For refractory hemoptysis, including after repeated bronchial artery embolization, consider surgery (lobectomy or pneumonectomy) if there is adequate pulmonary reserve.

For refractory pneumothorax with persistent air leak and no resolution of the pneumothorax, additional chest tubes and/or pleurodesis should be attempted. Pleurodesis can be attempted using a combination of mechanical and chemical means.

For refractory pancreatitis, investigate for pseudocysts or other complicating factors and consider prolonged TPN.

For DIOS consider using interventional radiology for gastrografin enemas (similar process to barium enemas), where the gastrografin can be placed close to the obstruction, avoiding the need for surgical exploration; and surgery should be a last resort.

5. Disease monitoring, follow-up and disposition

Respiratory failure due to a typical CF exacerbation will usually respond to aggressive care with improvement in hypercapnea, decrease in sputum production and thickness, and coughing intensity. The best determinant of success is pre-respiratory failure lung function.

Respiratory failure due to pneumothorax usually has a good prognosis; however, in advanced disease, the prognosis is worse.

Hemoptysis usually has a good prognosis, once the problem is resolved; however, in severe disease the hemoptysis might be recurrent and sometimes lethal.

DIOS has a good prognosis, but recurrence is common.

Pancreatitis has a good prognosis, but it can recur. Note, patients can become pancreatic insufficient after recurrent episodes.

Once the respiratory failure is resolved, patients will no longer typically require ICU level care. If unable to be discharged to home, transfer to a lower-level inpatient unit or a rehabilitation facility. Follow-up should occur in a CF clinic. The same is true for most cases of respiratory failure due to pneumothorax or hemoptysis. When appropriate, in severe disease without any obvious contraindications to lung transplant, a referral to the transplant center should also be considered.

Pathophysiology

CF is caused by dysfunction of a protein named CFTR (cystic fibrosis transmembrane conductance regulator), which is a large chloride channel. The disease is inherited in autosomal recessive fashion and there are multiple genetic defects that can lead to CFTR dysfunction to differing degrees. Inadequate transport of chloride leads to viscous secretions in every exocrine gland in the body, including lungs, gastrointestinal tract, pancreas, liver, sinuses and the vas deferens.

Thick secretions lead to dysfunction of many organs; in the majority ofpatients the exocrine pancreas is fibrosed and destroyed at birth. Inapproximately 10% of patients the exocrine pancreas functions, but theyare prone to recurrent bouts of pancreatitis.

Epidemiology

Cystic fibrosis is the most common life-limiting genetic disease in the Caucasian population

It is an autosomal recessive disease, so the CFTR (cystic fibrosis transmembrane regulator) gene must have mutations on the copies of both parents for the disease to be evident

The gene is present in 1/30 persons of European descent; it is present but less common in African Americans and Hispanics, but even less common in Asian Americans.

There are approximately 30,000 patients in the United States; the vast majority are diagnosed in early childhood (now they are mainly diagnosed via newborn screening), but a small percentage with milder symptoms can be diagnosed as adults, including geriatric age.

Over 90% of the patients are Caucasian.

The disease can have very different degrees of severity across the patient population.

Certain genotypes predispose to more severe disease, but other not-yet-identified genetic modifiers, environmental factors and adherence can play a significant role in the disease phenotype (lung disease, pancreatic sufficiency vs. insufficiency, presence of diabetes, liver disease).

Patients are frequently infected with Pseudomonas (mucoid and non-mucoid phenotype) and with Staphylococcus aureus (MSSA and less frequently MRSA), Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, non-tuberculous mycobacteria (mainly MAC and M. abscessus) are increasing in prevalence, but are less common.

Diabetes is present in 35% of patients over the age of 30.

Liver disease is rare and only present in approximately 5% of severe cases.

Other problems include osteoporosis, severe sinus disease with nasal polyps and recurrent episodes of acute pancreatitis in pancreatic-sufficient patients.

Most patients have pancreatic insufficiency at birth and their exocrine pancreas is destroyed, requiring oral enzymes to digest food.

In children, thick mucus can lead to meconium ileus at birth.

In adults, especially in cases of dehydration, thick inspissated secretions can lead to distal intestinal obstruction syndrome (DIOS), which is characterized by significant amounts of stool in the terminal ileum and requires special attention to avoid surgery. Hydration, PEG solutions (Miralax or Golytely are examples) and use of enemas can help avoid surgery.

Prognosis

Patients with CF admitted with respiratory failure have a poor to fair prognosis; this is influenced by their level of lung function prior to respiratory failure; however, prognosis improves as lung function improves.

The prognosis for patients admitted with a pneumothorax and hemoptysis depends primarily on the severity of the underlying lung function prior to admission.

Presence of diabetes can complicate the prognosis.

Malnutrition and other organ dysfunction can also influence the prognosis.

The expected median survival of all current patients in the US Registry is 40.7 years.

The mean age of patients who die is 27.5 years.

Special considerations for nursing and allied health professionals.

Respiratory therapy plays an integral role in providing nebulized medications and airway clearance in a timely fashion.